CN114364684A - Heterocyclic compounds - Google Patents

Abstract

The present invention provides novel heterocyclic compounds having the general formulae (Ia) and (Ib),

Description

Heterocyclic compounds

Technical Field

The present invention relates to organic compounds useful for the treatment or prevention of a mammal, and in particular to monoacylglycerol lipase (MAGL) inhibitors useful for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, abdominal pain associated with irritable bowel syndrome and/or visceral pain in a mammal.

Background

Endocannabinoids (ECs) are lipid signals that exert their biological effects by interacting with cannabinoid receptors (CBR), CB1 and CB 2. They regulate a variety of physiological processes including neuroinflammation, neurodegenerative diseases and tissue regeneration (Iannotti, f.a. et al, Progress in lipid research 2016, 62, 107-28). In the brain, the main endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase (MAGL). MAGL can hydrolyze 85% of 2-AG; the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, d.k. et al, Science 2011, 334, 809). MAGL is expressed throughout the brain and in most brain Cell types, including neurons, astrocytes, oligodendrocytes, and microglia (Chanda, p.k. et al, Molecular pharmacology 2010, 78, 996; viewer, a. et al, Cell reports 2015, 12, 798). 2-AG hydrolyzes to form Arachidonic Acid (AA), the precursors of Prostaglandins (PG) and Leukotrienes (LT). Increased AA oxidative metabolism in inflamed tissues. The inflammatory process involves two major enzymatic reaction pathways for the oxidation of arachidonic acid, namely cyclooxygenase to produce PG and 5-lipoxygenase to produce LT. Among the various cyclooxygenase products formed during inflammationPGE2 is one of the most important products. These products have been detected at sites of inflammation (e.g., in the cerebrospinal fluid of patients with neurodegenerative diseases) and are thought to contribute to the inflammatory response and disease progression. 2-AG hydrolase activity in the nervous system of mice lacking MAGL (Mgll-/-) is significantly reduced, while 2-AG levels are elevated, while other arachidonic acid-containing phospho-and neutral lipids (including arachidonic Acid Ethanolamine (AEA) and other free fatty acids) remain unchanged. In contrast, the levels of prostaglandins and other eicosanoids derived from AA and AA derivatives, including prostaglandin E2(PGE2), D2(PGD2), F2(PGF2) and thromboxane B2(TXB2), were greatly reduced. Phospholipase A₂(PLA₂) Has been considered as a major source of AA, but cPLA₂The brain levels of AA in the deficient mice were unchanged, thus enhancing the critical role of MAGL in the brain in regulating the processes of AA production and encephalitis.

Neuroinflammation is a common pathological feature of brain diseases including, but not limited to, neurodegenerative diseases (e.g., multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins controls neuroinflammatory processes. The pro-inflammatory agent Lipopolysaccharide (LPS) results in a steady time-dependent increase in brain eicosanoid production, a phenomenon that is markedly attenuated in Mgll-/-mice. LPS treatment also caused a general elevation of proinflammatory cytokines including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a) (inhibited in Mgll-/-mice).

Neuroinflammation is characterized by the activation of innate immune cells, microglia, and astrocytes of the central nervous system. Anti-inflammatory drugs have been reported to inhibit glial Cell activation and progression of disease, including alzheimer's disease and multiple sclerosis, in preclinical models (Lleo, a., Cell Mol Life sci.2007, 64, 1403). Importantly, genetic and/or pharmacological disruption of MAGL activity also blocks LPS-induced microglial activation in the brain (Nomura, d.k. et al, Science 2011, 334, 809).

Furthermore, genetic and/or pharmacological disruption of MAGL activity has been demonstrated to have protective effects in animal models of various neurodegenerative diseases, including but not limited to alzheimer's disease, parkinson's disease, and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegenerative diseases (Long, j.z. et al, Nature chemical biology 2009, 5, 37). Systemic injection of such inhibitors can reproduce the phenotype of Mgll-/-mice in the brain, including increased 2-AG levels, decreased AA levels and associated eicosanoid production, and prevent cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, d.k. et al, Science 2011, 334, 809), completely confirming MAGL as a drug target.

Endogenous levels of the natural substrate 2-AG of MAGL are increased in the brain as a genetic and/or pharmacological disruption of MAGL activity occurs. It has been reported that 2-AG exhibits a beneficial effect on pain, for example, an analgesic effect on mice (Ignatowska-Jankowska, b. et al, j. pharmacol. exp. ther.2015, 353, 424), and also a beneficial effect on mental disorders (e.g., depression in chronic stress models) (Zhong, p. et al, Neuropsychopharmacology 2014, 39, 1763).

In addition, Oligodendrocytes (OL), myelin sheath cells of the central nervous system and their precursors (OPC) express cannabinoid receptor 2(CB2) on their membranes. 2-AG is an endogenous ligand for the CB1 and CB2 receptors. Pharmacological inhibition of both cannabinoids and MAGL has been reported to attenuate the vulnerability of excitotoxic attacks of OL and OPC and may therefore have neuroprotective effects (Bernal-Chico, a. et al, gia 2015, 63, 163). Furthermore, pharmacological inhibition of MAGL increased the number of myelin OLs in the brain of mice, suggesting that MAGL inhibition can promote OPC differentiation in myelin OLs in vivo (Alpar, a. et al, Nature communications 2014, 5, 4421). Inhibition of MAGL has also been shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu, a. et al, Journal of Neuroscience 2017, 37, 8385).

In addition, in recent years, metabolism, particularly lipid metabolism, has received high attention in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have shown that endocannabinoids have anti-tumor effects, including anti-proliferative, apoptosis-inducing, and anti-metastatic effects. MAGL acts as an important catabolic enzyme in the lipid metabolism and endocannabinoid system and as an integral part of the gene expression profile, affects different aspects of tumorigenesis (including in glioblastoma) (Qin, h. et al, Cell biochem. biophysis.2014, 70, 33; Nomura DK et al, Cell 2009, 140(1), 49-61; Nomura DK et al, chem. biol.2011, 18(7), 846-.

The endocannabinoid system is also involved in a number of physiological and physiopathological effects in the gastrointestinal tract (Marquez l. et al, PLoS One 2009, 4(9), e 6893). All of these effects are driven primarily by cannabinoid receptors (CBR) CB1 and CB 2. The CB1 receptor is present throughout the GI tract of animals and healthy humans, particularly in smooth muscle cells of the Enteric Nervous System (ENS) and epithelial linings, as well as blood vessels in the colon wall (Wright K. et al, Gastroenterology 2005, 129(2), 437 453; Duncan, M. et al, animal Pharmacol Ther 2005, 22(8), 667 683). Activation of CB1 produces antiemetic, peristaltic inhibition and anti-inflammatory effects and helps to regulate pain (perietti, a. et al, Ann Gastroenterol 2020, 33(2), 134-. The CB2 receptor is expressed in immune cells such as plasma cells and macrophages, as well as in the lamina propria of the GI tract (Wright k. et al, Gastroenterology 2005, 129(2), 437-453) and is expressed predominantly on the epithelium of human colon tissue associated with Inflammatory Bowel Disease (IBD). Activation of CB2 exerts an anti-inflammatory effect by reducing pro-inflammatory cytokines. MAGL expression in colonic tissue of UC patients is increased (Marquez l. et al, PLoS One 2009, 4(9), e6893) and 2-AG levels in plasma of IBD patients are increased (Grill, m. et al, Sci Rep 2019, 9(1), 2358). Multiple animal studies demonstrate the potential of MAGL inhibitors in the symptomatic treatment of IBD. MAGL inhibits TNBS-induced colitis in mice by CB1/CB2 MoA and reduces local circulating inflammatory markers (Marquez l. et al, PLoS One 2009, 4(9), e 6893). In addition, MAGL inhibition of MoA driven by CB1 improves gut wall integrity and gut permeability (Wang, J. et al, Biochem Biophys Res Commun 2020, 525(4), 962-.

In summary, inhibition of the action and/or activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, inflammatory bowel disease, abdominal pain, and abdominal pain associated with irritable bowel syndrome. Furthermore, inhibition of the action and/or activation of MAGL is a promising new therapeutic strategy to provide neuroprotection and remyelination. Thus, there is an unmet urgent medical need for novel MAGL inhibitors.

Disclosure of Invention

In a first aspect, the present invention provides novel heterocyclic compounds having the general formulae (Ia) and (Ib)

Or a pharmaceutically acceptable salt thereof, wherein A, B and L are as described herein.

In another aspect, the present invention provides a process for the production of a urea compound of formula (Ia) or (Ib) as described herein, which process comprises:

reacting the first amine 4a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] [1, 4] oxazin-3-one (1)

With a second amine of formula 2, wherein A, L and B are as described herein,

in the presence of a base and a urea-forming agent,

to form said compound of formula (Ia) or (Ib).

In another aspect, the present invention provides a compound of formula (Ia) or (Ib) as described herein, produced according to the process described herein.

In another aspect, the present invention provides a compound of formula (Ia) or (Ib) as described herein for use as therapeutically active substance.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or (Ib) as described herein and a therapeutically inert carrier.

In another aspect, the present invention provides the use of a compound of formula (Ia) or (Ib) as described herein or a pharmaceutical composition as described herein for inhibiting monoacylglycerol lipase (MAGL) in a mammal.

In another aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition as described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

In another aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition described herein for the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-associated spasm, abdominal pain, irritable bowel syndrome-associated abdominal pain and/or visceral pain in a mammal.

Detailed Description

Definition of

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The term "alkyl" refers to a monovalent or multivalent (e.g., monovalent or divalent) straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms ("C)_1-6-alkyl "), for example 1, 2, 3, 4, 5 or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2, 2-dimethylpropyl. Particularly preferred, but non-limiting examples of alkyl groups are methyl and tert-butyl.

The term "alkoxy" means an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, alkoxy groups contain 1 to 12 carbon atoms. In some preferred embodiments, the alkoxy group contains 1 to 6 carbon atoms ("C)_1-6-alkoxy "). In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy group is methoxy.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

The term "cyano" refers to the group — CN (butyronitrile).

The term "hydroxy" refers to an-OH group.

The term "alkylsulfonyl" refers to through SO₂The alkyl group, as defined hereinbefore, attached to the parent molecular moiety.

The term "carbamoyl" refers to the group H₂N-C(O)-。

The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced with a hydroxyl group. Preferably, "hydroxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms (most preferably 1 hydrogen atom) of the alkyl group have been replaced by a hydroxyl group. Preferred but non-limiting examples of hydroxyalkyl groups are hydroxymethyl and hydroxyethyl (e.g., 2-hydroxyethyl). A particularly preferred but non-limiting example of a hydroxyalkyl group is 2-hydroxyethyl.

The term "alkoxyalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group wherein 1, 2, or 3 hydrogen atoms, and most preferably 1 hydrogen atom, of the alkyl group has been substituted with an alkoxy group. A preferred but non-limiting example of an alkoxyalkyl group is 2-methoxyethyl.

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C)₃-C₁₀-cycloalkyl "). In some preferred embodiments, cycloalkyl groups are saturated monocyclic hydrocarbon groups having 3 to 8 ring carbon atoms. "bicyclic cycloalkyl" refers to cycloalkyl moieties consisting of two saturated carbocyclic rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) as well as spirocyclic moieties (i.e., the two rings are connected via one common ring atom). Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, system having 3 to 14 ring atoms, preferably 4 to 7 ring atoms, wherein 1, 2 or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, the remaining ring atoms being carbon. More preferably, one of the ring atoms is N and the remaining ring atoms are carbon. "bicyclic heterocyclyl" refers to heterocyclic moieties consisting of two rings having two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) as well as spirocyclic moieties (i.e., the two rings are connected via one common ring atom). Some non-limiting examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-azaspiro [3.3] heptanyl, and 2, 3, 3a, 4, 6, 6 a-hexahydro-1H-pyrrolo [3, 4-c ] pyrrolyl. Preferred, but non-limiting examples of heterocyclyl groups include azetidin-1-yl, 2-azaspiro [3.3] heptan-2-yl, 2, 3, 3a, 4, 6, 6 a-hexahydro-1H-pyrrolo [3, 4-c ] pyrrol-5-yl and 7-azaspiro [3.5] nonan-7-yl. One particularly preferred, but non-limiting example of a heterocyclyl group includes azetidin-1-yl.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl groups include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of an aryl group is phenyl.

The term "heteroaryl" refers to a monovalent or polyvalent monocyclic or bicyclic (preferably monocyclic) ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5 to 10 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5 to 10 membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1, 2-benzoxazol-3-yl, 1, 2-benzoxazol-4-yl, 1, 2-benzoxazol-5-yl, 1, 2-benzoxazol-6-yl, 1, 2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, and mixtures thereof, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. Particularly preferred but non-limiting examples of heteroaryl groups are pyridyl, especially 3-pyridyl, and oxazolyl, especially oxazol-2-yl.

The term "haloalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred, but non-limiting, example of haloalkyl is trifluoromethyl (CF)₃) And trifluoroethyl (e.g., 2, 2, 2-trifluoroethyl).

The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred, but non-limiting, example of a haloalkoxy group is trifluoromethoxy (-OCF)₃)。

The term "haloaryl" refers to an aryl group in which at least one hydrogen atom of the aryl group has been replaced with a halogen atom, preferably fluorine or chlorine. Preferably, "haloaryl" refers to an aryl group in which 1, 2 or 3 hydrogen atoms of the aryl group have been replaced with a halogen atom (most preferably fluorine). A particularly preferred but non-limiting example of a haloaryl group is 4-fluorophenyl.

The term "aryloxy" refers to an aryl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. A preferred but non-limiting example of an aryloxy group is phenoxy.

The term "cycloalkyloxy" refers to a cycloalkyl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. A preferred but non-limiting example of a cycloalkoxy group is cyclopropoxy.

The term "heteroaryloxy" refers to a heteroaryl group, as previously defined, appended to the parent molecular moiety through an oxygen atom. A preferred but non-limiting example of a heteroaryloxy group is a pyridyloxy group (e.g., 2-pyridyloxy).

The term "heterocyclyloxy" refers to a heterocyclyl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. A preferred but non-limiting example of a heterocyclyloxy group is pyrrolidinyloxy (e.g., pyrrolidin-3-yl-oxy).

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effects and properties of the free base or free acid, which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like (particularly hydrochloric acid) and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like). A particular pharmaceutically acceptable salt of a compound of formula (Ia) or (Ib) is the hydrochloride salt.

As used herein, the term "protecting group" (PG) means selectivityA group that blocks a reactive site in a multifunctional compound to selectively chemically react at another unprotected reactive site with which it is normally associated in synthetic chemistry. The protecting group may be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups. A specific protecting group is tert-butoxycarbonyl (B)_oc) Benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Other specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in the following documents: T.W.Greene and P.G.M.Wutts, Protective Groups in Organic Chemistry, 5 th edition, 2014, John Wiley&Sons，New York。

As used herein, the term "urea former" refers to a compound that is capable of converting a first amine into a substance that can react with a second amine to form a urea derivative. Non-limiting examples of urea-forming agents include bis (trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, and 1, 1' -carbonyldiimidazole. Urea forming agents such as those described by Sartori, g. et al (Green Chemistry 2000, 2, 140), which is incorporated herein by reference.

The compounds of formula (Ia) or (Ib) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms may be in either the "R" or "S" configuration.

The abbreviation "MAGL" refers to monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

The term "treating" as used herein includes: (1) inhibiting the state, disorder or condition of at least one clinical or subclinical symptom of the disease (e.g., arresting, reducing, or delaying the progression of the disease or its recurrence in the context of maintenance therapy); and/or (2) remission (i.e., resolution of the state, disorder or condition of the disease or at least one of its clinical or subclinical symptoms). The benefit to the patient to be treated is statistically significant or at least perceptible to the patient or physician. However, it is understood that when a drug is administered to a patient to treat a disease, the results may not always be an effective treatment.

The term "control" as used herein includes: preventing or delaying the onset of clinical symptoms of a state, disorder or condition that develops in a mammal, particularly a human, that may be afflicted with or susceptible to the state, disorder or condition but that has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder or condition.

As used herein, the term "neuroinflammation" relates to acute and chronic inflammation of neural tissue, which is the major tissue component of both parts of the nervous system; the brain and spinal cord of the Central Nervous System (CNS) and the branched peripheral nerves of the Peripheral Nervous System (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as alzheimer's disease, parkinson's disease and multiple sclerosis. Acute neuroinflammation typically occurs immediately after injury to the central nervous system, e.g., as a result of Traumatic Brain Injury (TBI).

As used herein, the term "traumatic brain injury" ("TBI", also referred to as "intracranial injury") relates to brain injury caused by external mechanical forces such as rapid acceleration or deceleration, shock wave, or projectile penetration.

As used herein, the term "neurodegenerative disease" relates to a disease associated with progressive loss of structure or function of neurons (including neuronal death). Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis.

As used herein, the term "psychiatric disorder" (also known as psychosis or psychosis) relates to behavioral or mental patterns that may cause distress or poor lifestyle. Such features may be persistent, recurrent or palliative, or may be a single event. Examples of psychiatric disorders include, but are not limited to, anxiety and depression.

As used herein, the term "pain" refers to the unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain (including chemotherapy-induced neuropathy), phantom pain, and psychogenic pain. One particular example of pain is neuropathic pain, which results from injury or disease affecting any part of the nervous system (i.e., the somatosensory system) that involves physical sensation. In one embodiment, "pain" is neuropathic pain resulting from amputation or open chest surgery. In one embodiment, "pain" is chemotherapy-induced neuropathy.

As used herein, the term "neurotoxicity" refers to toxicity of the nervous system. This occurs when exposure to natural or artificial toxic substances (neurotoxins) alter the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity caused by exposure to substances used in chemotherapy, radiotherapy, pharmacotherapy, drug abuse, and organ transplantation, as well as exposure to heavy metals, certain food and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some natural substances.

As used herein, the term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor due to the growth of abnormally uncontrolled cells (such cells are "cancer cells"). As used herein, the term cancer specifically includes, but is not limited to hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

The term "mammal" as used herein includes humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cows, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to a human.

Compounds of the invention

In a first aspect (A1), the present invention provides a compound of formula (Ia) or (Ib)

Or a pharmaceutically acceptable salt thereof, wherein:

a is by R^AA substituted 3-to 14-membered heterocycle;

b is by R¹、R²And R³Substituted C₆-C₁₄-aryl or 5-to 14-membered heteroaryl;

l is selected from the group consisting of a covalent bond, -C.ident.C-, -CHR^L-、-CH₂CHR^L-、-O-、-OCH₂-and-CH₂O-; and is

R¹、R²And R³Independently selected from hydrogen, halogen, cyano, C₁-C₆-alkylsulfonyl, R^bR^cN、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄-aryl, C₃-C₁₀-cycloalkyl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy, wherein said C is₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy are optionally independently selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy and carbamoyl substituted with one or more substituents;

R^Aselected from hydrogen and C₁-C₆-an alkyl group;

R^band R^cIndependently selected from hydrogen, C₁-C₆-alkyl radicalAnd C₆-C₁₄-an aryl group; and is

R^LSelected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆Alkyl, alkoxy-C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₆-C₁₄Aryl and halo-C₆-C₁₄-an aryl group.

The present invention also provides the following enumerated example (E) of the first aspect of the invention (a 1):

E1. a compound of formula (Ia) or (Ib) according to a1, wherein:

a is by R^AA substituted 3-to 14-membered heterocycle;

b is by R¹、R²And R³Substituted C₆-C₁₄-aryl or 5-to 14-membered heteroaryl;

l is selected from the group consisting of a covalent bond, -C.ident.C-, -CHR^L-、-CH₂CHR^L-、-O-、-OCH₂-and-CH₂O-; and is

R¹、R²And R³Independently selected from hydrogen, halogen, cyano, C₁-C₆-alkylsulfonyl, R^bR^cN、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, C₆-C₁₄-aryl, C₃-C₁₀-cycloalkyl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy, wherein said C is₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy are optionally independently selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy and carbamoyl substituted with one or more substituents;

R^Aselected from hydrogen and C₁-C₆-an alkyl group;

R^band R^cIndependently selected from hydrogen, C₁-C₆-alkyl and C₆-C₁₄-an aryl group; and is

R^LSelected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆Alkyl, alkoxy-C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₆-C₁₄Aryl and halo-C₆-C₁₄-an aryl group.

E2. A compound of formula (Ia) or (Ib) according to A1 or E1 or a pharmaceutically acceptable salt thereof, wherein

A is a 3-to 14-membered heterocyclic ring;

b is by R¹、R²And R³Substituted C₆-C₁₄-an aryl group;

l is selected from the group consisting of a covalent bond, -CH₂-、-CH₂CH₂-、-OCH₂-and-CH₂O-; and is

R¹、R²And R³Independently selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl and C₆-C₁₄-aryl is optionally independently selected from halogen and halo-C₁-C₆-one or more substituents of alkyl.

E3. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ia) or (Ib) is not selected from:

(4aS, 8aS) -6- [4- [ [4- (trifluoromethyl) phenyl ] methyl ] piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one;

(4aR, 8aR) -6- [4- [ [4- (trifluoromethyl) phenyl ] methyl ] piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one; and

rac- (4aS, 8aS) -6- [4- (2-methylallyl) piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one (CAS 1941372-36-6).

E4. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein a is a 4-9 membered heterocyclic ring wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.

E5. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, wherein a is a 4-9 membered heterocyclic ring wherein one of the ring atoms is nitrogen and the remaining ring atoms are carbon, or a pharmaceutically acceptable salt thereof.

E6. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein a is a 4-9 membered heterocyclic ring selected from azetidin-1-yl, 2-azaspiro [3.3] heptan-2-yl, 2, 3, 3a, 4, 6, 6 a-hexahydro-1H-pyrrolo [3, 4-c ] pyrrol-5-yl and 7-azaspiro [3.5] nonan-7-yl.

E7. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, wherein a is a 4-8 membered heterocyclic ring wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon, or a pharmaceutically acceptable salt thereof.

E8. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, wherein a is a 4-8 membered heterocyclic ring wherein one of the ring atoms is nitrogen and the remaining ring atoms are carbon, or a pharmaceutically acceptable salt thereof.

E9. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein a is a 4-8 membered heterocyclic ring selected from azetidin-1-yl, 2-azaspiro [3.3] heptan-2-yl and 2, 3, 3a, 4, 6, 6 a-hexahydro-1H-pyrrolo [3, 4-c ] pyrrol-5-yl.

E10. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein a is azetidine or 7-azaspiro [3.5] nonan-7-yl.

E11. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein a is azetidine.

E12. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E11 or a pharmaceutically acceptable salt thereof, wherein R^AIs hydrogen.

E13. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E12, or a pharmaceutically acceptable salt thereof, wherein B is substituted with R¹、R²And R³A substituted phenyl group.

E14. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein:

l is selected from the group consisting of a covalent bond, -CHR^L-、-CH₂CH₂-、-O-、-OCH₂-and-CH₂O-; and is

R^LIs hydrogen or halo-C₆-C₁₄-an aryl group.

E15. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond, -O-, -CH₂-、-CH₂CH₂-、-OCH₂-and-CH₂O-。

E16. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E13 or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond, -CH₂-、-CH₂CH₂-、-OCH₂-and-CH₂O-。

E17. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E13 or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond, -CH₂CH₂-and-CH₂O-。

E18. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond or-O-.

E19. A compound of formula (Ia) or (Ib) as described in any one of a1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond.

E20. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl.

E21. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl, C₆-C₁₄Aryloxy group and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl.

E22. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C₆-C₁₄Aryloxy and halogeno-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group.

E23. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C₆-C₁₄-aryloxy, halo-C₁-C₆-alkyl and halogenated-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group.

E24. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Selected from phenoxy and (trifluoromethyl) cyclopropyl.

E25. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E19 or a pharmaceutically acceptable salt thereof, wherein R¹Selected from phenoxy, CF₃And (trifluoromethyl) cyclopropyl。

E26. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E25 or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen and halogen.

E27. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E25 or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen and fluorine.

E28. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E25 or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

E29. A compound of formula (Ia) or (Ib) according to any one of A1 and E1 to E28 or a pharmaceutically acceptable salt thereof, wherein R³Is hydrogen.

E30. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

R¹is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl; and is

R²Selected from hydrogen and halogen.

E31. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

R¹selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein saidC₃-C₁₀-cycloalkyl, C₆-C₁₄Aryloxy group and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl; and is

R²Selected from hydrogen and halogen.

E32. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹Substituted C₆-C₁₄-an aryl group; and is

R¹Is selected from C₆-C₁₄Aryloxy and halogeno-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group.

E33. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

R¹is selected from C₆-C₁₄-aryloxy, halo-C₁-C₆-alkyl and halogenated-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group; and is

R²Selected from hydrogen and halogen.

E34. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹Substituted phenyl; and is

R¹Selected from phenoxy and (trifluoromethyl) cyclopropyl.

E35. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E29, or a pharmaceutically acceptable salt thereof, wherein:

b is by R¹And R²Substituted phenyl;

R¹selected from phenoxy, CF₃And (trifluoromethyl) cyclopropyl; and is

R²Is hydrogen or fluorine.

E36. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

l is selected from the group consisting of a covalent bond, -CH₂CH₂-、-CHR^L-, -O-and-CH₂O-；

R^LIs hydrogen or halo-C₆-C₁₄-an aryl group;

R¹selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl, C₆-C₁₄Aryloxy group and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl; and is

R²Selected from hydrogen and halogen.

E37. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

l is selected from the group consisting of a covalent bond, -CH₂CH₂-and-CH₂O-；

R¹Is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl; and is

R²Selected from hydrogen and halogen.

E38. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

l is a covalent bond or-O-;

R¹is selected from C₆-C₁₄-aryloxy, halo-C₁-C₆-alkyl and halogenated-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group; and is

R²Is hydrogen or halogen.

E39. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹Substituted C₆-C₁₄-an aryl group;

l is a covalent bond; and is

R¹Is selected from C₆-C₁₄Aryloxy and halogeno-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group.

E40. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is azetidine or 7-azaspiro [3.5] nonan-7-yl;

b is by R¹And R²Substituted phenyl;

l is selected from the group consisting of a covalent bond, -CH₂-or-O-;

R¹selected from phenoxy, CF₃And (trifluoromethyl) cyclopropyl; and is

R²Is hydrogen or fluorine.

E41. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E3, or a pharmaceutically acceptable salt thereof, wherein:

a is azetidine;

b is by R¹Substituted phenyl;

l is a covalent bond; and is

R¹Selected from phenoxy and (trifluoromethyl) cyclopropyl.

E42. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E41, or a pharmaceutically acceptable salt thereof, selected from the compounds disclosed in table 1.

E43. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E41, or a pharmaceutically acceptable salt thereof, selected from:

(4aR, 8aR) -6- [3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

(4aS, 8aS) -6- (3- (4-phenoxyphenyl) azetidine-1-carbonyl) hexahydro-2H-pyrido [4, 3-b ] [1, 4] oxazin-3 (4H) -one

(-) -or (+) -trans-6- [2- [ 2-fluoro-4- (trifluoromethyl) phenoxy ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

E44. A compound of formula (Ia) or (Ib) according to any one of a1 and E1 to E41, or a pharmaceutically acceptable salt thereof, selected from:

(4aR, 8aR) -6- [3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

(4aS, 8aS) -6- (3- (4-phenoxyphenyl) azetidine-1-carbonyl) hexahydro-2H-pyrido [4, 3-b ] [1, 4] oxazin-3 (4H) -one

In a particular embodiment, the present invention provides pharmaceutically acceptable salts of compounds of formula (Ia) or (Ib) as described herein. In another particular embodiment, the present invention provides a compound of formula (Ia) or (Ib), as described herein, which is a free base.

In some embodiments, the compounds of formula (Ia) or (Ib) are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Such isotopically (i.e., radiolabeled) compounds of formula (Ia) or (Ib) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (Ia) or (Ib) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, respectively, such as but not limited to²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. certain isotopically-labeled compounds of formula (Ia) or (Ib) (e.g., those comprising a radioisotope) are useful in drug and/or matrix tissue distribution studies. Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) This is particularly useful because they are easily incorporated and the detection means are readily available. For example, a compound of formula (Ia) or (Ib) may be enriched in 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of a given isotope.

With heavier isotopes such as deuterium (i.e.,²H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

With positron-emitting isotopes (such as¹¹C、¹⁸F、¹⁵O and¹³n) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labelled compounds of formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples set out below using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used.

Production method

The preparation of the compounds of formula (Ia) or (Ib) according to the invention can be carried out sequentially or via convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to perform the reaction and to purify the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the methods have the meanings provided herein.

If the starting material, intermediate or one of the compounds of formula (Ia) or (Ib) contains one or more functional Groups which are unstable or reactive under the reaction conditions of the reaction step or steps, suitable protecting Groups may be introduced prior to the critical step using methods well known in the art (as described in T.W.Greene and P.G.M.Wutts, "Protective Groups in Organic Chemistry", 5 th edition, 2014, John Wiley & Sons, New York). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

If the starting materials or intermediates contain stereogenic centers, the compounds of formula (Ia) or (Ib) can be obtained in the form of diastereomers or mixtures of enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC, or chiral crystallization). Racemic compounds can be separated, for example, into the corresponding counterparts by separation of the diastereomeric salts, by crystallization from optically pure acids, or by separation of the enantiomers by specific chromatography using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can likewise be isolated to provide diastereomerically/enantiomerically enriched starting materials and intermediates. The use of such diastereomer/enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (Ia) or (Ib) typically results in corresponding diastereomer/enantiomer-enriched compounds of formula (Ia) or (Ib).

One skilled in the art will recognize that an "orthogonal protecting group strategy" will be applied in the synthesis of compounds of formula (Ia) or (Ib), if not desired, which allows cleavage of multiple protecting groups at a time without affecting the other protecting groups in the molecule. The principles of orthogonal protection are well known in the art and are also described in the literature (e.g., Barany, G., Merrifield, R.B., J.Am.chem.Soc.1977, 99, 7363; Waldmann, H. et al, Angew.chem.Iht.Ed.Engl.1996, 35, 2056).

One skilled in the art will recognize that the order of the reactions may vary depending on the reactivity and nature of the intermediates.

In more detail, the compounds of formula (Ia) or (Ib) can be produced by the methods described below, in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Also, see, for example, the literature for reported reaction conditions that affect the reaction: "Comprehensive Organic Transformations: a Guide to Functional Group Preparations, Richard C.Larock, 2 nd edition, 1999, John Wiley & Sons, N.Y.). It is convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents, at least to some extent. The reaction described can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The above reaction can be conveniently carried out at a temperature ranging from-78 ℃ to reflux. The time required for the reaction can also vary widely, depending on a number of factors, in particular the reaction temperature and the nature of the reagents. However, it usually takes from 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps may be freely changed according to the starting materials and their corresponding reactivity.

If starting materials or intermediates are not commercially available or their synthesis is not reported in the literature, they can be prepared using existing methods of preparation similar to the close analogs or as outlined in the experimental section.

The following abbreviations are used in this text:

AcOH acetic acid, Boc t-butoxycarbonyl, CAS RN chemical abstracts accession number, Cbz benzyloxycarbonyl, DME dimethoxyethane, DMF N, N-dimethylformamide, DIPEA N, N-diisopropylethylamine, ESI electrospray ionization, EtOAc ethyl acetate, EtOH ethanol, H₂Water, HCl, HPLC, IPA, 2-propanol, K₂CO₃Potassium carbonate, K₃PO₄Tripotassium phosphate, LiHMDS lithium bis (trimethylsilyl) amide, MgSO₄Magnesium sulfate, min mL, MPLC medium pressure liquid chromatography, MS mass spectrum, NaH sodium hydride, NaHCO₃Sodium bicarbonate, NaOH, Na₂CO₃Sodium carbonate, Na₂SO₄Sodium n-butyl lithium n-butyl sulfate, NEt₃Triethylamine (TEA), NH₄Cl ═ ammonium chloride, OAc ═ acetoxy, PG ═ protective group, Pd/C ═ activated palladium on carbon, Pd (OH)₂Palladium hydroxide, R ═ any group, rt ═ room temperature, SFC ═ supercritical fluid chromatography, TEA ═ triethylamine, TFA ═ trifluoroacetic acid, THF ═ tetrahydrofuran.

Compounds of formula I wherein A, B and L are as described herein can be prepared according to methods analogous to those described in the literature and/or asScheme 1The synthesis as described in (1).

Scheme 1

Thus, the compounds are used in the presence of urea formers such as bis (trichloromethyl) carbonateSuitable bases and solvents such as sodium bicarbonate, 4a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] in DCM][1，4]Reaction of oxazin-3-one 1 with intermediate 2 to give a compound of formula I (Step a). Other urea forming agents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, or 1, 1' -carbonyldiimidazole. Such reactions and the use of these reagents are widely described in the literature (e.g., Sartori, g. et al, Green Chemistry 2000, 2, 140). Those skilled in the art will recognize that the order of addition of reagents may be important in such reactions due to the reactivity and stability of the intermediate formed carbamoyl chloride and to avoid the formation of an undesirable symmetrical urea by-product in the following manner.

Can be as follows for exampleScheme 2Intermediate 1 was synthesized as shown and/or similar to the methods described in the literature.

Scheme 2

Thus, 3-aminopiperidin-4-ol derivative 3 wherein "PG" represents a suitable protecting group such as Cbz or Boc protecting group may be acylated, for example, with chloroacetyl chloride or bromoacetyl chloride 4 wherein "LG" represents a suitable leaving group (e.g., Cl or Br), by reaction in a suitable base such as sodium or potassium carbonate, sodium hydroxide or sodium acetate using a suitable solvent such as THF, water, acetone or mixtures thereof to give intermediate 5 (c: (r) (r))Step a)。

Intermediate 5 can be cyclized to intermediate 6 using methods well known in the art, such as by treatment of sodium hydride in THF or IPA and potassium tert-butoxide in water 5 ((R))Step b). Such reactions are described in the literature (e.g., Rafinski, Z. et al, J. org. chem.2015, 80, 7468; Dugar, S. et al, Synthesis 2015, 47, 712; WO 2005/066187).

Removal of the protecting group in intermediate 6 is carried out using methods known in the art (e.g., using TFA in DCM at a temperature between 0 ℃ and room temperature or inRemoval of Boc group by HCl in dioxane or diethyl ether or 4-methylbenzenesulfonic acid hydrate in ethyl acetate or mixtures thereof; in the presence of a suitable catalyst such as Pd on activated carbon or Pd (OH) in a suitable solvent such as MeOH, EtOH, ethyl acetate, or mixtures thereof₂Removing the Cbz group with hydrogen; and are described, for example, in the following documents: t.w.greene and p.g.m.wuts, "Protective Groups in Organic Chemistry", 4 th edition, 2006, Wiley, New York) to afford intermediate 1 (aStep c)。

Intermediate 1 may be obtained as a mixture of diastereomers and enantiomers, or as a single stereoisomer, depending on whether a racemic mixture or an optically pure form of cis-or trans-3-aminopiperidin-4-ol derivative 3 is employed in the synthesis. Intermediate 3 is commercially available and methods for its synthesis are also described in the literature (e.g., WO 2005/066187; WO 2011/0059118; WO 2016/185279).

Can be for example based onScheme 3The optically pure trans-configuration intermediates 1B and 1C were obtained. The appropriately protected rac-trans-4 a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] is chirally separated using methods known in the art, e.g. by crystallization of diastereomeric salts or by chiral chromatography][1，4]Oxazin-3-ones (7) ("PG" denotes a suitable protecting group such as Cbz or Boc) to give enantiomerically pure stereoisomers 8 and 9: (C and CStep a). Removal of the protecting groups in intermediates 8 and 9 is carried out using methods known in the art (e.g., removal of the Boc group using TFA in DCM or HCl in dioxane or diethyl ether at a temperature between 0 ℃ and room temperature; in a suitable solvent such as MeOH, EtOH, ethyl acetate or mixtures thereof in the presence of a suitable catalyst such as Pd on activated carbon or Pd (OH))₂Removing the Cbz group with hydrogen; and are described, for example, in the following documents: t.w.greene and p.g.m.wuts, "Protective Groups in Organic Chemistry", 4 th edition, 2006, Wiley, New York) to give intermediates 1B and 1C in pure trans configuration.

Scheme 3

In some embodiments, intermediate 2 is a type II intermediate, wherein m and n are as described herein, B is an optionally further substituted aryl or heteroaryl ring, and R is¹To R³Each independently selected from hydrogen, substituted or unsubstituted (cyclo) alkyl, (cyclo) alkoxy, substituted or unsubstituted aryl, R^bR^cN, cyano, heterocycle, methylsulfonyl, and halogen, wherein substituted alkyl, aryl, and heteroaryl are as defined herein, R^bIs hydrogen, alkyl or aryl, and R^cIs alkyl or aryl, or R^bAnd R^cTogether with the nitrogen atom to which they are attached form an optionally further substituted 4-11 membered monocyclic or bicyclic heterocyclic ring. Such intermediates can be prepared by methods well known in the art and as suchScheme 4The general synthetic procedures outlined in (a) above.

Scheme 4

Commercially available intermediate 10 (where PG represents a suitable protecting group and X is bromide or iodide) may be reacted with compound 11 (commercially available or prepared by methods known in the art where FG represents a suitable functional group such as chlorine, bromine, iodine, -OSO)₂Alkyl (e.g., methanesulfonate (methanesulfonate)), -OSO₂Fluoroalkyl (e.g., trifluoromethanesulfonate (trifluoromethanesulfonate)) or-OSO₂Aryl groups (e.g., tosylate (p-toluenesulfonate)) undergo cross-coupling reactions, such as Negishi, Heck, Stille, Suzuki, Sonogashira or Buchwald-Hartwig coupling reactions: (Step a). Such reactions are widely described in the literature and are well known to those skilled in the art.

For example, intermediate 10 may be reacted with an arylboronic acid or heteroarylboronic acid 11a (FG ═ b (oh)₂) Or boric acid esters 11b (FG is, for example, 4, 5, 5-tetramethyl-2-phenyl-1, 3, 2-dioxaborole)Alkyl (pinacol) esters; commercially available or available literature procedures (e.g., "Boronic Acids-Preparation and Applications in Organic Synthesis and Medicine", ed. by Dennis G.Hall, 1 st edition, 2005, John Wiley&Sons, New York) reaction using a suitable catalyst (e.g., dichloro [1, 1' -bis (diphenylphosphino) -ferrocene)]Palladium (II) dichloromethane adduct, tetrakis (triphenylphosphine) palladium (0) or palladium (II) acetate with triphenylphosphine) in a suitable solvent (e.g. dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof) or a suitable base (e.g. Na)₂CO₃、NaHCO₃、KF、K₂CO₃Or TEA) at a temperature between room temperature and the boiling point of the solvent or solvent mixture to give intermediate 12 (C: (C)Step a). Such Suzuki reactions are widely described in the literature (e.g., Suzuki, a., Pure appl. chem.1991, 63, 419; Suzuki, a., Miyaura, n., chem.rev.1995, 95, 2457; Suzuki, a., j. organomet. chem.1999, 576, 147; Polshettiwar, n., Decottignies, a., Len, c., Fihri, a., ChemSusChem 2010, 3, 502) and are well known to those skilled in the art. Alternatively, an aryltrifluoroborate or heteroaryltrifluoroborate 11c (FG ═ BF)₃) Can be used in cross-coupling reactions using palladium catalysts such as tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate or dichloro [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloromethane adduct) in the presence of a suitable base such as cesium carbonate or potassium phosphate, in a solvent such as toluene, THF, dioxane, water or mixtures thereof at a temperature between room temperature and the boiling point of the solvent or solvent mixture.

Alternatively, intermediate 10 may be reacted with an arylstannane or heteroarylstannane 11d (where FG is Sn (alkyl)₃And alkyl is preferably n-butyl or methyl), using a suitable catalyst and solvent, such as tetrakis (triphenylphosphine) -palladium (0) in DMF, at a temperature between room temperature and the boiling point of the solvent or solvent mixture to give intermediate 12 (b: (b) ((iii)), (iii)Step a). Such Stille reactions are well known in the art and are described, for example, in the following documentsThe method comprises the following steps: farina, v., Krishnamurthy, v., Scott, w.j., org.reach.1997, 50, 1-652; cordvila, c., Bartolom é, c., marti inez-Ilarduya, j.m., Espinet, p., ACS catal.2015, 5, 3040.

In addition, intermediate 10 may be reacted with an aryl or heteroaryl zinc halide 11e (where FG is ZnHal, and Hal is preferably bromide or iodide, which may be commercially available or prepared using literature reported methods) using an appropriate catalyst and solvent system (such as [1, 1' -bis (diphenylphosphino) ferrocene in DMA)]Dichloropalladium (II) and copper (I) iodide or tetrakis (triphenylphosphine) palladium (0) in THF or DMF) at a temperature between room temperature and the boiling point of the solvent to give intermediate 12 (I)Step a). Such Negishi reactions are well known in the art and are described, for example, in the following documents: gayryuhin, a., Kofink, c., Manolikakes, g., Knochel, p., org.lett.2005, 7, 4871; haas, d., Hammann, j.m., Greiner, r., Knochel, p., ACS catal.2016, 6, 1540; negishi, e. -i, acc, chem, res, 1982, 15, 340.

Alternatively, intermediate 12 may be prepared by the following method: the literature reported methods are applied to convert intermediate 10, where X is, for example, iodide, to the corresponding zinc species (e.g., reaction of 10 with Zn powder in the presence of chlorotrimethylsilane and 1, 2-di-bromoethane in a suitable solvent such as DMA) and coupling the zinc species with aryl or heteroaryl bromide or iodide under the conditions described above.

Alternatively, intermediate 10 (wherein X is preferably bromide) may be cross-electrophilically coupled with aryl bromide or heteroaryl bromide 11f (wherein FG represents bromide) under 420nm blue-light irradiation, using a suitable photocatalyst such as bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl ] using a suitable photocatalyst]Phenyl radical]Iridium (1+) 4-tert-butyl-2- (4-tert-butyl-2-pyridyl) pyridium hexafluorophosphate (Ir [ dF (CF)₃)ppy]₂(dtbbpy))PF₆) Nickel catalysts such as NiCl₂Glyme (nickel dichloro (dimethoxyethane)), 4 '-di-tert-butyl-2, 2' -bipyridyl, and tris (trimethylsilyl) silane in the presence of a suitable base (such as anhydrous)Sodium carbonate) in a solvent such as DME. Such reactions are described, for example, in the following documents: zhang, p., Le, c., MacMillan, d.w.c., j.am.chem.soc.2016, 138, 8084 (Zhang, lo)Step (ii) of a)。

Applications are well known in the art and are asScheme 2Examples of (A) to (B)Step c) The protecting group in intermediate 12 was removed by the method described in (1) to give intermediate II: (Step b)。

Intermediate 12 can alternatively be prepared from intermediate 10 and aryl bromide or heteroaryl bromide 13 (commercially available or prepared by methods known in the art), using the methods described aboveStep aThe conversion process described in (1) to give intermediate 14: (Step c)。

Intermediate 14 may alternatively be prepared from intermediate 10 and arylboronic acid or heteroarylboronic acid 16a (FG ═ b (oh)₂) Or boronic esters 16b (FG is, for example, 4, 5, 5-tetramethyl-2-phenyl-1, 3, 2-dioxaborolan (pinacol) ester) (commercially available or prepared using methods known in the art) using nickel mediated alkyl-aryl Suzuki coupling reactions, which are well known in the art and also described, for example, in the following documents: dunton, m.a.j., estaarte, m.a., Tan, d., Kaub, c., O' Mahony, d.j.r., Johnson, r.j., Cox, m., Edwards, w.t., Wan, m., kinaid, j., Kelly, m.g., org.lett.2008, 10, 3259; gonz lez-Bobes, F, Fu, G.C., J.Am.chem.Soc.2006, 128, 5360 (F, G.C.)Step e)。

Intermediate 14 can be further reacted with compound 15, wherein the above appliesStep aThe same synthetic strategy as described in (1) to give intermediate 12: (b)Step d)。

Intermediate 12 (wherein R³Represents R^bR^cAmine group of the N type, wherein R^bIs hydrogen, alkyl or aryl and R^cIs alkyl or aryl, or wherein R^bAnd R^cTogether with the nitrogen atom to which they are attached form an optionally further substituted 4-11 membered monocyclic or bicyclic heterocycle) can be reacted, for example via 14, with a primary or secondary amine R^bR^cNH reaction synthesis using, for example, suitableCatalysts (e.g. Pd (OAc)₂、Pd₂(dba)₃) Ligands (e.g., BINAP, Xphos, Brettphos, RuPhos), bases (e.g., Cs)₂CO₃、K₂CO₃、KOt-Bu、LiHMDS、K₃PO₄) And a solvent (e.g., toluene, THF, dioxane). Such Negishi reactions are known in the art and are described in the literature (e.g., Surry, d.s., Buchwald, s.l., angew.chem.int.ed.2008, 47, 6338; Evano, g., Blanchard, n., Toumi, m., chem.rev.2008, 108, 3054; Heravi, m.m., kheikkori, z., Zadsirjan, v., Heydari, m., malm, m.j.organomet.chem.2018, 861, 17) ((e.g., Surry, d.s., Buchwald, et al., bulwald, et al., zaldi, Zadsirjan, v., Heydari, m.m.Step d)。

Type III intermediates (wherein RL is as defined herein) can be prepared by various conditions, which can be achieved byScheme 5The general synthetic procedure outlined in (1).

Scheme 5

Intermediate 18 can be prepared by olefination reactions such as the widely reported Wittig or Homer-Wadsworth-emmons (hwe) reaction using phosphonium salt or phosphonate carbanions 20a or 20b aldehyde or ketone 19 (commercially available or prepared by methods known in the art).

Wittig reaction with 20a type alkylenetriphenylphosphane in a suitable solvent such as THF, methyl-THF or DMSO to give intermediate 18 (step a). The phosphine alkane 20a may be formed by treating the corresponding phosphonium salt with a suitable base such as BuLi, NaH or KOtBu in a suitable solvent such as THF, dioxane or methyl-THF, and may be isolated or used in situ. The phosphonium salt may then be readily obtained from an aryl halide 17 (wherein LG is a halogen selected from Cl, Br or I, and B is as defined herein) and triphenylphosphine in a suitable solvent such as toluene (step aa). Heat may be applied to accelerate or drive the reaction to completion (h.j. cristauu, f.plenat, PATAI' S Chemistry of Functional Groups, Frank r. hartley (master eds), 8.7.2006, Saul PATAI (staph).

Alternatively, intermediate 18 may be obtained using a Homer-Wadsworth-Emmons (HWE) reaction using an aldehyde/ketone 19 and a phosphonate 20b, wherein R is^aIs an alkyl group, such as methyl or ethyl. The phosphonate 20b is subjected to in situ alpha-metallation (step a) using a suitable base and solvent, such as NaH, nBuLi or KOtBu in THF. Phosphonates 20B are readily prepared by alkylation of an aryl halide 17 (wherein LG is a halogen selected from Cl, Br or I and B is as defined herein) with a commercially available trialkyl phosphite using, for example, the Arbuzov reaction (step ab, see, for example, Brill, t.b., Landon, s.j., chem.rev.1984, 84, 577).

Both types of olefination reactions are widely described in the literature (e.g., Maryanoff, B.E., Reitz, A.B., chem.Rev.1989, 89, 863; Boutagy, J., Thomas, R., chem.Rev.1974, 74, 87; Bischeglia, J.A., Orelli, L.R., Current org.chem.2015, 19, 744; Wadsworth Jr., W.S., Org.React.1977, 25, 73; Nicolaou, K.C., 863; U.S.; B.R.,

M.W.，Gunzner，J.L.，Nadin，A.，Liebigs Ann./Recueil 1997，1283；Stec，W.J.，Acc.Chem.Res.1983，16，411)(step a)。

The double bond in intermediate 18 may be present, for example, at atmospheric pressure in the presence of a suitable catalyst (such as Pd (OH))₂Or Pd/C) in a suitable solvent (such as MeOH, EtOH or EtOAc or mixtures thereof) to afford intermediate 21: (Step b)。

Applications are well known in the art and are asScheme 2Examples of (A) to (B)Step c) The protecting group in intermediate 21 was removed by the method described in (1) to give intermediate III: (Step c)。

The type IV intermediate can be prepared by various conditions, which can be determined byScheme 6The general synthetic procedure outlined in (1).

Scheme 6

Using aryl halide or heterobenzyl halide 17 (where LG is selected from Cl, Br or I and B is as defined herein) as a starting material, intermediate 22 can be prepared by an olefination reaction such as the widely reported Wittig or Homer-Wadsworth-Emmons (HWE) reaction using a phosphonium salt or phosphonate carbanion reacted with spirocyclic ketone 21 (commercially available or prepared by methods known in the art), as described above (Step a)。

The double bond in intermediate 22 may be present, for example, at atmospheric pressure in the presence of a suitable catalyst (such as Pd (OH))₂Or Pd/C) in a suitable solvent (such as MeOH, EtOH or EtOAc or mixtures thereof) to afford intermediate 23: (Step b)。

Applications are well known in the art and are asScheme 2Examples of (A) to (B)Step c)The protecting group in intermediate 23 was removed by the method described in (1) to give intermediate IV: (Step c)。

Intermediates of form V (wherein RL is as defined herein) can be prepared by various conditions, which can be determined byScheme 7The general synthetic procedure outlined in (1).

Scheme 7

Intermediate 26 can be prepared from alcohols 25, where PG is a suitable protecting group such as Cbz, Boc or Bn, which can be alkylated with compound 24, where LG is a suitable leaving group such as chloro, bromo, iodo, OSO₂Alkyl (e.g., methanesulfonate), OSO₂Fluoroalkyl (e.g. triflate) or OSO₂Aryl (e.g. p-toluenesulphonate), reaction using a suitable base such as sodium hydride, KOtBu in a suitable solvent (e.g. DMF or THF) at a temperature between 0 ℃ and the boiling point of the solvent: (Step a)。

Applications are well known in the art and are asScheme 2Examples of (A) to (B)Step c)The protecting group in intermediate 23 was removed by the method described in (1) to give intermediate V: (Step b)。

In one aspect, the present invention provides a process for the production of a urea compound of formula (Ia) or (Ib) as described herein, the process comprising:

reacting the first amine 4a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] [1, 4] oxazin-3-one (1)

With a second amine of formula 2, wherein A, L and B are as described herein,

in the presence of a base and a urea-forming agent,

to form said compound of formula (Ia) or (Ib).

In one embodiment, there is provided a process according to the invention, wherein the base is sodium bicarbonate.

In one embodiment, there is provided a method according to the present invention, wherein the urea forming agent is selected from bis (trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate and 1, 1' -carbonyldiimidazole, preferably wherein the urea forming agent is bis (trichloromethyl) carbonate.

In one aspect, the present invention provides a compound of formula (Ia) or (Ib) as described herein, produced according to any one of the methods described herein.

Inhibitory Activity of MAGL

The compounds of the present invention are MAGL inhibitors. Accordingly, in one aspect, the present invention provides the use of a compound of formula (Ia) or (Ib) as described herein for inhibiting MAGL in a mammal.

In another aspect, the present invention provides a compound of formula (Ia) or (Ib) as described herein for use in a method of inhibiting MAGL in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ia) or (Ib) as described herein for the manufacture of a medicament for inhibiting MAGL in a mammal.

In another aspect, the present invention provides a method of inhibiting MAGL in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (Ia) or (Ib) as described herein.

The inhibitory activity of compounds on MAGL was assayed by measuring the enzyme activity after hydrolysis of the natural substrate 2-arachidonoyl glycerol to arachidonic acid, and mass spectrometry was then performed. This assay is hereinafter abbreviated as "2-AG assay".

The 2-AG assay was performed in 384 well assay plates (PP, Greiner Cat. No. 784201) in a total volume of 20. mu.L. Compound dilutions were prepared in 100% DMSO (VWR Chemicals 23500.297) in polypropylene plates using a 3-fold dilution procedure to give final concentrations ranging from 12.5 μ M to 0.8pM for the assay. mu.L of compound dilution (100% DMSO) was added to 9. mu.L of assay buffer for MAGL (50mM TRIS (GIBCO, 15567-027), 1mM EDTA (Fluka, 03690-100ml) and 0.01% (v/v) Tween). After shaking, the plates were incubated at room temperature for 15 min. The reaction was started by adding 10. mu.L of a solution of 2-arachidonoyl glycerol in assay buffer. The final concentrations in this assay were 50pM MAGL and 8. mu.M 2-arachidonoyl glycerol. After shaking and incubation at room temperature for 30min, 40 μ L of ACN containing 4 μ M d 8-arachidonic acid was added to quench the reaction. The arachidonic acid content was followed using an online SPE system (Agilent Rapidfire) in combination with a triple quadrupole mass spectrometer (Agilent 6460). In the ACN/water liquid setup, a C18 SPE cartridge (G9205A) was used. The mass spectrometer was operated in negative electrospray mode with the mass ion pair for arachidonic acid 303.1 → 259.1 and the mass ion pair for d 8-arachidonic acid 311.1 → 267.0. The activity of the compounds was calculated based on the intensity ratio of [ arachidonic acid/d 8-arachidonic acid ].

TABLE 1

In one aspect, the present invention provides a compound of formula (Ia) or (Ib) as described herein and pharmaceutically acceptable salts thereof, wherein said compound of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof have a MAGL inhibitory IC of less than 25 μ M, preferably less than 10 μ M, more preferably less than 5 μ M as measured in the MAGL assay described herein₅₀。

In one embodiment, compounds of formula (Ia) or (Ib) as described herein and pharmaceutically acceptable salts thereof have an IC of between 0.000001 μ Μ and 25 μ Μ₅₀(MAGL inhibition) value, specific compounds having an IC between 0.000005. mu.M and 10. mu.M₅₀Values, more specific compounds have an IC between 0.00005. mu.M and 5. mu.M₅₀Values, which are measured in the MAGL assay described herein.

Using the compounds of the invention

In one aspect, the present invention provides a compound of formula (I) as described herein for use as therapeutically active substance.

In another aspect, the invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing neuroinflammation and/or neurodegenerative disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of a neurodegenerative disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of cancer in a mammal.

In one embodiment, the invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of pain in a mammal.

In one aspect, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain associated with irritable bowel syndrome, and/or visceral pain in a mammal.

In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prophylaxis of multiple sclerosis, alzheimer's disease and/or parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of cancer in a mammal.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of a neurodegenerative disease in a mammal.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of pain in a mammal.

In one aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain associated with irritable bowel syndrome, and/or visceral pain in a mammal.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative disorders, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of neuroinflammation and/or neurodegenerative disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of a neurodegenerative disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of cancer in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of inflammatory bowel disease in a mammal.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of pain in a mammal.

In another aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-related spasm, abdominal pain, irritable bowel syndrome-related abdominal pain and/or visceral pain in a mammal.

In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, alzheimer's disease and/or parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein in the manufacture of a medicament for the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal, which method comprises administering to the mammal an effective amount of a compound of formula (I) as described herein.

In one embodiment, the present invention provides a method for treating or preventing neuroinflammation and/or neurodegenerative disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as described herein.

In one embodiment, the present invention provides a method for treating or preventing a neurodegenerative disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as described herein.

In one embodiment, the present invention provides a method for treating or preventing cancer in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

In one embodiment, the invention provides a method for treating or preventing inflammatory bowel disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

In one embodiment, the present invention provides a method for treating or preventing pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

In another aspect, the present invention provides a method for treating or preventing multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon canceration, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain associated with irritable bowel syndrome, and/or visceral pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

In a preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as described herein.

In a particularly preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as described herein.

Pharmaceutical compositions and administration

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or (Ib) as described herein and a therapeutically inert carrier.

In one embodiment, the present invention provides pharmaceutical compositions as disclosed in examples 32 and 33, respectively.

Compounds of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof are useful as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical formulations may be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be by parenteral such as intramuscular or intravenous (e.g. in the form of an injection).

The compounds of formula (Ia) or (Ib) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants to produce tablets, coated tablets, dragees and hard gelatine capsules. For example, lactose, corn starch or derivatives thereof (talc, stearic acid or its salts, etc.) can be used as such auxiliaries for tablets, dragees and hard gelatin capsules.

Suitable auxiliaries for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols and the like.

Suitable auxiliaries for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable auxiliaries for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer masks or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will, of course, be fitted to the requirements in each particular case. Generally, in case of oral administration, a daily dose of about 0.1 to 20mg per kg body weight, preferably about 0.5 to 4mg per kg body weight (e.g. about 300mg per person) (divided into preferably 1-3 individual doses which may e.g. consist of the same amount) should be suitable. It will be apparent, however, that the upper limit given herein can be exceeded when shown as labeled.

Examples of the invention

The invention will be more fully understood by reference to the following examples. However, the claims should not be construed as limited to the scope of the embodiments.

Where the preparative examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

All reaction examples and intermediates were prepared under argon atmosphere if not otherwise stated.

Examples 1 and 2

(+) -or (-) -trans-6- [3- (4-tert-butylphenyl) azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

And

(-) -or (+) -trans-6- [3- (4-tert-butylphenyl) azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

To rac-trans-hexahydro-2H-pyrido [4, 3-b ]][1，4]To a solution of oxazin-3 (4H) -one hydrochloride (49.8mg, 233. mu. mol, 1.0 equiv.; BB 1) and trimethylamine (145mg, 200. mu.L, 1.43mmol, 6.2 equiv.) in acetonitrile (1.0mL) was added 1, 1' -carbonyl-bis (1, 2, 4-triazole) (38.2mg, 233. mu.L, 1.0 equiv.), and the reaction mixture was stirred at room temperature. After 1h, add3- (4- (tert-butyl) phenyl) azetidine 4-methylbenzenesulfonate (84.1mg, 233. mu. mol, eq 1.0; BB 2) and stirring was continued at 50 ℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the desired product as a white solid (42.8mg, 50%). Enantiomers were separated using chiral SFC (Chiralpak AD-H chromatography column, 220nm, 5 μm, 250 × 20mm) to give example 1(11.0mg, 13%; first eluting isomer) and example 2(11.0mg, 13%; second eluting isomer) as white solids. In two examples, ms (esi): 372.3[ M + H ] M/z]⁺。

Examples 3 and 4

(+) -or (-) -trans-6- [3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

And

(-) -or (+) -trans-6- [3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

To rac-trans-hexahydro-2H-pyrido [4, 3-b ]][1，4]To a solution of oxazin-3 (4H) -one hydrochloride (49.8mg, 233. mu. mol, 1.0 equiv.; BB 1) and trimethylamine (145mg, 200. mu.L, 1.43mmol, 6.2 equiv.) in acetonitrile (1.0mL) was added 1, 1' -carbonyl-bis (1, 2, 4-triazole) (38.2mg, 233. mu.L, 1.0 equiv.), and the reaction mixture was stirred at room temperature. After 1h, 3- [4- [1- (trifluoromethyl) cyclopropyl ] was added]Phenyl radical]Azetidine 4-methylbenzenesulfonate (96.3mg, 233. mu. mol, eq.1.0; BB 3) and stirring was continued at 50 ℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the desired product as a white solid (60.6mg, 55%). The enantiomers were separated using chiral SFC (Chiralpak AD-H column, 220nm, 5 μm, 250X 20min) to give example 3(12.9mg, 23%; first eluting isomer) and example 4(12.1mg, 22%; second eluting isomer),it is a white solid. In two examples, ms (esi): 424.4[ M + H ] M/z]⁺。

Examples 5 and 6

(+) -or (-) -trans-6- [3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methoxy ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

And

(-) -or (+) -trans-6- [3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methoxy ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

To an ice-cold solution of bis (trichloromethyl) carbonate (97mg, 0.33mmol, 0.7 equiv.) in DCM (4mL) was added sodium bicarbonate (157mg, 1.87mmol, 4.0 equiv.) and 3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] sodium bicarbonate]Methoxy radical]Azetidine 4-methylbenzenesulfonic acid (236mg, 561. mu. mol, 1.2 equiv.; BB 4), and the reaction mixture was stirred at room temperature. After 8H, rac-trans-hexahydro-2H-pyrido [4, 3-b ] was added][1，4]Oxazin-3 (4H) -one hydrochloride (90mg, 467 μmol, 1.0 equiv; BB 1) and DIPEA (242mg, 326 μ L, 1.87mmol, 4.0 equiv) and stirred at room temperature for 5H. The reaction mixture was poured into water and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was washed twice with water and over MgSO₄Dried, filtered and evaporated. The crude product was purified by preparative HPLC to give the desired product as a colourless solid (86mg, 42%). Enantiomers were separated using chiral SFC (Chiralpak AD-H chromatography column, 220nm, 5 μm, 250 × 20mm) to give example 5(41mg, 51%; first eluting isomer) and example 6(36mg, 45%; second eluting isomer) as light brown solids. In example 5, ms (esi): m/z 432.3[ M + H ]]⁺(ii) a In example 6, ms (esi): m/z 432.2[ M + H ]]⁺。

Example 7

(+) -or (-) -trans-6- [3- [ 3-chloro-4- (trifluoromethoxy) phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

To (+) -trans-hexahydro-2H-pyrido [4, 3-b ]][1，4]To a solution of oxazin-3 (4H) -one hydrochloride (17.3mg, 90 μmol, 1.0 equiv; BB5A) and trimethylamine (64.2mg, 89 μ L, 630 μmol, 7.0 equiv) in acetonitrile (1.0mL) was added 1, 1' -carbonyl-bis (1, 2, 4-triazole) (14.8mg, 90 μmol, 1.0 equiv), and the reaction mixture was stirred at room temperature. After 1h, 3- [ 3-chloro-4- (trifluoromethoxy) phenyl ] was added]Azetidine 2, 2, 2-trifluoroacetic acid (39.5mg, 108. mu. mol, eq.1.2; CAS RN 1260891-17-5), and stirring was continued at 60 ℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the desired product as an off-white solid (3.4mg, 9%). Ms (esi): m/z 434.3[ M + H ═ M]⁺。

Example 8

(-) -or (+) -trans-6- [3- [ 3-chloro-4- (trifluoromethoxy) phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

To (-) -trans-hexahydro-2H-pyrido [4, 3-b ]][1，4]To a solution of oxazin-3 (4H) -one hydrochloride (17.3mg, 90 μmol, 1.0 equiv; BB 5B) and trimethylamine (64.2mg, 89 μ L, 630 μmol, 7.0 equiv) in acetonitrile (1.0mL) was added 1, 1' -carbonyl-bis (1, 2, 4-triazole) (14.8mg, 90 μmol, 1.0 equiv), and the reaction mixture was stirred at room temperature. After 1h, 3- [ 3-chloro-4- (trifluoromethoxy) phenyl ] was added]Azetidine 2, 2, 2-trifluoroacetic acid (39.5mg, 108. mu. mol, eq.1.2; CAS RN 1260891-17-5), and stirring was continued at 60 ℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the desired product as an off-white solid (2.6mg, 7%). Ms (esi):m/z＝434.3[M+H]⁺。

the following examples were synthesized using appropriate building blocks in a manner similar to the synthesis described for examples 7 and 8, respectively, if not otherwise indicated.

Synthesis of building blocks

BB 1

rac-trans-hexahydro-2H-pyrido [4, 3-b ] [1, 4] oxazin-3 (4H) -one hydrochloride

Step 1: rac-trans-3- [ (2-chloroacetyl) amino]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

Trans-3-amino-1-boc-4 was inward-directed at 3 hours at room temperature by a syringe pumpTo a suspension of hydroxypiperidine (1.01g, 4.69mmol, 1.0 equiv; CAS RN 1268511-99-4) and sodium acetate trihydrate (1.28g, 9.38mmol, 2.0 equiv) in a mixture of acetone (8mL) and water (1mL) was added 2-chloroacetyl chloride (0.53g, 0.37mL, 4.69mmol, 1.0 equiv) dropwise. The reaction mixture was evaporated and the crude product was purified by silica gel chromatography using MPLC system eluting with a gradient of n-heptane: EtOH/ethyl acetate (1: 3) (70: 30 to 10: 90) to give the title compound as a colorless foam (0.44g, 64%). Ms (esi): 237.1[ M +2H-tBu ] M/z]⁺。

Step 2: rac-trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ]][1，4]Oxazine-6- (iv) Carboxylic acid tert-butyl ester

To ice-cold rac-trans-3- [ (2-chloroacetyl) amino]To a solution of tert-butyl (4-hydroxy-piperidine-1-carboxylate (1.18g, 4.03mmol, 1.0 equiv.) in DCM (18mL) was added dropwise a solution of potassium tert-butoxide (1.81g, 16.1mmol, 4.0 equiv.) in 2-propanol (46 mL). The ice bath was removed and the mixture was stirred at room temperature for 24h to give a white suspension. The reaction mixture was evaporated and the residue was taken up in ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were over MgSO₄Dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using MPLC system, eluting with a gradient of DCM: methanol (100: 0 to 90: 10) to give the title compound as a colorless foam (0.84g, 75%). Ms (esi): m/z 201.1[ M +2H-tBu]⁺。

And step 3: rac-trans-hexahydro-2H-pyrido [4, 3-b][1，4]Oxazin-3 (4H) -one hydrochloride

To a solution of 2M HCl in ether (15.5mL, 31.0mmol, 10 equiv.) was added rac-trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ]][1，4]Oxazine-6-carboxylic acid tert-butyl ester (0.80g, 3.11mmol, 1.0 equiv) and the reaction mixture was stirred at room temperature for 24 h. The colourless suspension was cooled in the refrigerator to 0 ℃ and continued for 2h, the precipitate was filtered, washed with diethyl ether anddrying under vacuum. The title compound was obtained as a colorless solid (0.62g, 98%). Ms (esi): m/z 157.1[ M + H ]]⁺。

BB 2

3- (4- (tert-butyl) phenyl) azetidine 4-methylbenzenesulfonate

To a solution of tert-butyl 3- (4-tert-butylphenyl) azetidine-1-carboxylate (1.8g, 6.22mmol, 1.0 equiv.; CAS RN 1629889-13-9) in ethyl acetate (15mL) was added 4-methylbenzenesulfonic acid hydrate (1.66g, 8.70mmol, 1.4 equiv.) and the mixture was heated to reflux for 12 h. The solution was evaporated to give the title compound as a brown oil (1.69g, 66%). Ms (esi): 190.2[ M + H-Ts ] M/z]⁺。

BB 3

3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine 4-methylbenzenesulfonate

Step 1: 3- [4- (1- (trifluoromethyl) cyclopropyl ] amide]Phenyl radical]Azetidine-1-carboxylic acid tert-butyl ester

To a 20mL vial equipped with a stir bar was added 1-bromo-4- (1- (trifluoromethyl) cyclopropyl) benzene (561mg, 2.12mmol, 1.0 equiv; CAS RN 1227160-18-0), tert-butyl 3-iodoazetidine-1-carboxylate (600mg, 2.12mmol, 1.0 equiv; CAS RN 254454-54-1), tris (trimethylsilyl) silane (527mg, 653. mu.L, 2.12mmol, 1.0 equiv), photocatalyst bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl)]Phenyl radical]Iridium (1+) 4-tert-butyl-2- (4-tert-butyl-2-pyridyl) pyridium hexafluorophosphate (23.8mg, 21.2. mu. mol, 0.01 eq.; Ir [ dF (CF3) ppy]2(dtbbpy)) PF6, CAS RN 870987-63-6) and anhydrous sodium carbonate (449mg, 4.24mmol, 2.0 equiv). The vial was sealed and placed under Ar, then dimethoxyethane (9mL) was added. Adding into another vialNickel (II) chloride ethylene glycol dimethyl ether complex (4.65mg, 21.2. mu. mol, 0.01 equiv; CAS RN 29046-78-4) and 4, 4 '-di-tert-butyl-2, 2' -bipyridine (5.68mg, 21.2. mu. mol, 0.01 equiv). The vial was sealed, purged with Ar, and dimethoxyethane (4mL) was added. The pre-catalyst solution was sonicated for 5min, then 2mL of the solution was injected into the reaction vessel. The reaction mixture was degassed with Ar and irradiated with a blue LED lamp (420nm) for 1 h. The reaction was quenched by exposure to air, filtered, and the solvent was evaporated. The crude reaction mixture was purified by silica gel chromatography using the MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 70: 30) to give the title compound as a colorless solid (0.51g, 66%). Ms (esi): 286.1[ M +2H-tBu ] M/z]⁺。

Step 2: 3- [4- [1- (trifluoromethyl) cyclopropyl]Phenyl radical]Azetidine 4-methylbenzenesulfonate

To 3- [4- [1- (trifluoromethyl) cyclopropyl group]Phenyl radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (0.5g, 1.46mmol, 1.0 equiv.) in ethyl acetate (5mL) was added 4-methylbenzenesulfonic acid hydrate (0.29g, 1.54mmol, 1.1 equiv.), and the mixture was heated at reflux for 2 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate was washed with ethyl acetate and dried to give the title compound as a colorless solid (0.52g, 82%). Ms (esi): 242.2[ M + H ] M/z]⁺。

BB 4

3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methoxy ] azetidine 4-methylbenzenesulfonic acid

Step 1: 3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl]Methoxy radical]Azetidine-1-carboxylic acid tert-butyl ester

To an ice-cold solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.02g, 11.7mmol, 1.0 equiv.) in DMF (25mL) was added sodium hydride (0.56g, 12.8mmol, 1.1 equiv.) in portions(ii) a 55% in mineral oil) and the reaction mixture was stirred for 30 min. A solution of 1- (bromomethyl) -2-fluoro-4- (trifluoromethyl) benzene (3.0g, 11.7mmol, 1.0 equiv.) in DMF (5mL) was added dropwise to the reaction mixture and stirring continued at rt for 3 h. The reaction mixture was poured into saturated NH₄Aqueous Cl (70mL) and ethyl acetate (70mL) and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were over MgSO₄Dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 60: 40) to give the title compound as a light yellow oil (3.66g, 90%). Ms (esi): 294.1[ M +2H-tBu ] M/z]⁺。

Step 2: 3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl]Methoxy radical]Azetidine 4-methylbenzenesulfonic acidTo 3- [ [ 2-fluoro-4- (trifluoromethyl) phenyl]Methoxy radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (7.8g, 22.3mmol, 1.0 equiv) in ethyl acetate (130mL) was added 4-methylbenzenesulfonic acid hydrate (4.61g, 26.8mmol, 1.2 equiv) and the mixture was heated at reflux for 2 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate was washed with ethyl acetate and dried to give the title compound as a colorless solid (7.3g, 81%). Ms (esi): m/z 250.2[ M + H ]]⁺。

BB5A and BB 5B

(+) -trans-4 a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] [1, 4] oxazin-3-one hydrochloride and (-) -trans-4 a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] [1, 4] oxazin-3-one hydrochloride

Step 1: (+) -trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b][1，4]Oxazine-6-carboxylic acid Tert-butyl ester and (-) -yl-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] compounds][1，4]Oxazine-6-carboxylic acid tert-butyl ester

Enantiomers of tert-butyl rac-trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazine-6-carboxylate (3.93g, 13.4 mmol; BB 1, step 2) were separated by SFC (preparative: Chiralpak AD-H column, 220nm, 5 μm, 250X 20 mm; analytical: Chiralpak AD-H column, 220nm, 5 μm, 150X 4.6mm) using MeOH (20-40%) as co-solvent.

The second eluted enantiomer: (-) -trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b][1，4]Oxazine-6-carboxylic acid tert-butyl ester. Off-white foam (1.0g, 81%). Analytical SFC: t is t_R＝2.49min。[α]^D ₂₀-16.3 ° (c ═ 1.0 in MeOH). Ms (esi): m/z 201.1[ M +2H-tBu]⁺。

The first eluting enantiomer: (+) -trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b][1，4]Oxazine-6-carboxylic acid tert-butyl ester. Off-white foam (1.2g, 92%). Analytical SFC: t is t_R＝1.36min。[α]^D ₂₀+19.1 ° (c ═ 1.0 in MeOH). Ms (esi): m/z 201.1[ M +2H-tBu]⁺。

Step 2: (+) -trans-4 a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b][1，4]Oxazin-3-one hydrochloric acid Salt (BB5A) and (-) -trans-4 a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ]][1，4]Oxazin-3-one hydrochloride (BB) 5B)

To (-) -trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ]][1，4]To a solution of oxazine-6-carboxylic acid tert-butyl ester (1.0g, 3.89mmol, 1.0 equiv) in DCM (10mL) was added a solution of 4M HCl in dioxane (9.7mL, 38.9mmol, 10 equiv) and the reaction mixture was stirred at 5 ℃ for 1h then warmed to room temperature. After 16h, the solvent was evaporated, then the white precipitate was filtered, washed with ether and dried under vacuum. The title compound was obtained as a colorless solid (0.74g, 99%). [ alpha ] to]^D ₂₀+32.9 ° (c ═ 1.0 in MeOH). Ms (esi): m/z 157.1[ M + H ]]⁺。

To (+) -trans-3-oxo-4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ]][1，4]To a solution of oxazine-6-carboxylic acid tert-butyl ester (1.1g, 4.31mmol, 1.0 equiv) in DCM (10mL) was added a solution of 4M HCl in dioxane (10.8mL, 43.1mmol, 10 equiv) and the reaction mixture was stirred at 5 ℃ for 1h then warmed to room temperature. After 16h, the solvent was evaporated, then the white precipitate was filtered, washed with ether and dried under vacuum. The title compound was obtained as a colorless solid (0.82g, 99%). [ alpha ] to]^D ₂₀-31.8 ° (c ═ 1.0 in MeOH). Ms (esi): m/z 157.1[ M + H ]]⁺。

BB 6

3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethyl ] azetidine 4-methylbenzenesulfonic acid

Step 1: (2-fluoro-4- (trifluoromethyl) benzyl) phosphonic acid diethyl ester

A solution of 1- (bromomethyl) -2-fluoro-4- (trifluoromethyl) benzene (1.1g, 4.28mmol, 1.0 eq.; CAS RN 239087-07-1) in triethyl phosphite (1.78g, 1.83mL, 10.7 mmol; 2.5 eq.) was stirred at reflux for 3 h. The crude reaction mixture was purified by silica gel chromatography using MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 0: 100) to give the title compound as a colorless oil (0.83g, 62%). Ms (esi): 315.2[ M + H ] M/z]⁺。

Step 2: 3- [ (E) -2- [ 2-fluoro-4- (trifluoromethyl) phenyl]Vinyl radical]Azetidine-1-carboxylic acid tert-butyl ester

To an ice-cold suspension of sodium hydride (122mg, 2.8mmol, 1.1 equiv.; 55% in mineral oil) in THF (5mL) was added diethyl (2-fluoro-4- (trifluoromethyl) benzyl) phosphonate (800mg, 2.55mmol, 1.0 equiv.) in THF (5mL) over 5min, and the mixture was stirred at that temperature for 30 min. Adding 3-formyl azetidine-1-carboxylic acid dropwise to the light brown mixtureA solution of tert-butyl ester (472mg, 2.55mmol, 1.0 equiv.) in THF (2.5mL) and the reaction mixture was stirred at 0-6 ℃ for an additional 3 h. The reaction mixture was poured into water and ethyl acetate, and the layers were separated. The organic layer was washed once with brine, dried over MgSO4, filtered and treated with silica gel and evaporated. The compound was purified by silica gel chromatography using the MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 50: 50) to give the title compound as a colorless oil (0.61g, 69%). Ms (esi): m/z 290.1[ M +2H-tBu]⁺。

And step 3: 3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl]Ethyl radical]Azetidine-1-carboxylic acid tert-butyl ester

To the 3- [ (E) -2- [ 2-fluoro-4- (trifluoromethyl) phenyl group]Vinyl radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (607mg, 1.76mmol, 1.0 equiv) in a mixture of MeOH (7mL) and ethyl acetate (7mL) was added Pd/C10% (60mg, 1.76mmol, 1.0 equiv) and the reaction mixture was stirred under a hydrogen atmosphere (1bar) at room temperature for 4 h. The suspension was filtered through a pad of celite, washed with ethyl acetate and dried under vacuum. The title compound was obtained as a colorless oil (0.61g, 98%). Ms (esi): 292.1[ M +2H-tBu ] M/z]⁺。

And 4, step 4: 3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl]Ethyl radical]Azetidine 4-methylbenzenesulfonic acid

To 3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl]Ethyl radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (111mg, 0.32mmol, 1.0 equiv.) in ethyl acetate (1.2mL) was added 4-methylbenzenesulfonic acid hydrate (66mg, 0.38mmol, 1.2 equiv.), and the mixture was heated at reflux for 2 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate was washed with ethyl acetate and dried to give the title compound as a colorless solid (96mg, 72%). Ms (esi): 248.2[ M + H ] M/z]⁺。

BB 7

3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethyl ] azetidine 4-methylbenzenesulfonic acid

Step 1: 3- (4-bromophenyl) azetidine-1-carboxylic acid tert-ester

To a suspension of 3-iodoazetidine-1-carboxylic acid tert-butyl ester (2.0g, 7.06mmol, 1.0 equiv; CAS RN 254454-54-1) and (4-bromophenyl) organoboronic acid (2.84g, 14.1mmol, 2.0 equiv; CAS RN 5467-74-3) in 2-propanol (25mL) was added rac-trans-2-aminocyclohexan-1-ol (48.8mg, 424. mu. mol, 0.06 equiv.), nickel (II) iodide (132mg, 424. mu. mol, 0.06 equiv.) and sodium bis (trimethylsilyl) amide (6.48g, 14.1mmol, 2.0 equiv.; 40% in THF) at room temperature under Ar. The reaction mixture was heated to 80 ℃ with microwave radiation and held for 30 min. The mixture was then poured into water and ethyl acetate (containing insoluble solids), and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with MgSO₄Dried, filtered and treated with silica gel and evaporated. The compound was purified by silica gel chromatography using the MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 50: 50) to give the title compound as a colorless oil (1.33g, 60%). Ms (esi): 256.0[ M +2H-tBu ] M/z]⁺。

Step 2: 3- [4- (2, 4-di-fluorophenyl) phenyl]Azetidine-1-carboxylic acid tert-butyl ester

A suspension of tert-butyl 3- (4-bromophenyl) azetidine-1-carboxylate (1.3g, 4.16mmol, 1.0 equiv.), (2, 4-difluorophenyl) organoboronic acid (658mg, 4.16mmol, 1.0 equiv.; CAS RN 144025-03-6), potassium carbonate (2.88g, 20.8mmol, 5.0 equiv.), tetrakis (triphenylphosphine) palladium (0) (241mg, 208. mu. mol, 0.05 equiv.) in a mixture of THF (10mL) and water (1mL) was heated to 110 ℃ using microwave radiation and continued for 15 min. The mixture was then poured into water and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with MgSO₄Dried, filtered and treated with silica gel and evaporated. Purifying the extract by silica gel chromatographyThe compound was eluted using the MPLC system with a gradient of n-heptane to ethyl acetate (100: 0 to 50: 50) to give the title compound as a light yellow oil (1.20g, 79%). Ms (esi): m/z 290.2[ M +2H-tBu]⁺。

And step 3: 3- [2- [ 2-fluoro-4- (trifluoromethyl) phenyl]Ethyl radical]Azetidine 4-methylbenzenesulfonic acid

To the 3- [4- (2, 4-difluorophenyl) phenyl]To a solution of azetidine-1-carboxylic acid tert-butyl ester (1.20g, 3.47mmol, 1.0 equiv.) in ethyl acetate (5mL) was added 4-methylbenzenesulfonic acid hydrate (0.72g, 4.17mmol, 1.2 equiv.), and the mixture was heated at reflux for 2 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate was washed with ethyl acetate and dried to give the title compound as a colorless solid (0.92g, 63%). Ms (esi): 246.2[ M + H ] M/z]⁺。

BB 8

3- [4- (2, 2, 2-trifluoroethyl) phenyl ] azetidine 4-methylbenzenesulfonic acid

Step 1: 3- [4- (2, 2, 2-trifluoroethyl) phenyl]Chloretane-1-carboxylic acid tert-butyl ester

The product was obtained as a colorless oil in step 1 using 1-bromo-4- (2, 2, 2-trifluoroethyl) benzene (CAS RN 155820-88-5) in analogy to BB 3. Ms (esi): m/z 260.1[ M +2H-tBu]⁺。

Step 2: 3- [4- (2, 2, 2-trifluoroethyl) phenyl]Azetidine 4-methylbenzenesulfonic acid

To the 3- [4- (2, 2, 2-trifluoroethyl) phenyl group]To a solution of azetidine-1-carboxylic acid tert-butyl ester (0.98g, 3.09mmol, 1.0 equiv.) in ethyl acetate (12mL) was added 4-methylbenzenesulfonic acid hydrate (0.64g, 3.71mmol, 1.2 equiv.), and the mixture was heated at reflux for 2 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate is treated with ethyl acetateThe ester was washed and dried to give the title compound as a colourless solid (0.54g, 45%). Ms (esi): 216.1[ M + H ] M/z]⁺。

BB 9

6- [ (2, 4-difluorophenyl) methyl ] -2-azaspiro [3.3] heptane 2, 2, 2-trifluoroacetic acid

Step 1: (2, 4-Difluorobenzyl) triphenylphosphonium bromide

To a solution of triphenylphosphine (1.27g, 4.83mmol, 1.0 equiv.) in ACN (10mL) under Ar was added 1- (bromomethyl) -2, 4-difluorobenzene (1.0g, 4.83mmol, 1.0 equiv.; CAS RN 23915-07-3). The reaction mixture was stirred at 80 ℃ for 3h, then allowed to cool to room temperature. Methyl tert-butyl ether (100mL) was added and the suspension was stirred at room temperature for 30 min. The solid was filtered off, washed with methyl tert-butyl ether and dried. The title compound was obtained as a white solid (2.02g, 98%). Ms (esi): 439.2[ M + H ] M/z]⁺。

Step 2: 6- [ (2, 4-difluorophenyl) methylene]-2-azaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester

To a solution of (2, 4-difluorobenzyl) triphenylphosphonium bromide (1.7g, 3.62mmol, 1.0 equiv.) in dry THF (10mL) at-78 deg.C under Ar was added LiHMDS (7.24mL, 7.24mmol, 2.0 equiv.; 1M solution in THF), and the reaction mixture was stirred for 2 h. Then 6-oxo-2-azaspiro [3.3] is added at room temperature]Tert-butyl heptane-2-carboxylate (1.53g, 7.24mmol, 2.0 equiv.; CAS RN 1181816-12-5) and the mixture was stirred at 85 ℃ overnight. Methyl tert-butyl ether was added and the precipitate (triphenylphosphine oxide) was filtered off. The filtrate was concentrated and purified by silica gel chromatography using the MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 70: 30) to give the title compound as a white solid (0.35g, 30%). Ms (esi): 266.2[ M +2H-tBu ] M/z]⁺。

And step 3: 6- [ (2, 4-difluorophenyl) methyl group]-2-azaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester

To 6- [ (2, 4-difluorophenyl) methylene]-2-azaspiro [3.3]To a solution of tert-butyl heptane-2-carboxylate (0.35g, 1.09mmol, 1.0 equiv) in ethyl acetate (10mL) was added Pd/C10% (116mg, 0.11mmol, 0.1 equiv) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (1bar) for 2 h. The suspension was filtered through a pad of celite, washed with ethyl acetate and dried under vacuum. The title compound was obtained as a white solid (0.35g, 98%). Ms (esi): 268.2[ M +2H-tBu ] M/z]⁺。

And 4, step 4: 6- [ (2, 4-difluorophenyl) methyl group]-2-azaspiro [3.3]Heptane 2, 2, 2-trifluoroacetic acid

To 6- [ (2, 4-difluorophenyl) methyl]-2-azaspiro [3.3]To a solution of tert-butyl heptane-2-carboxylate (55mg, 170. mu. mol, 1.0 eq) in DCM (3mL) was added TFA (78mg, 52. mu.l, 680. mu. mol, 4.0 eq). The resulting reaction mixture was stirred at room temperature for 2h, then concentrated in vacuo (azeotroped with toluene). The title compound was obtained as a colorless oil and used directly in the next step without further purification (58mg, quantitative). Ms (esi): 224.2[ M + H ] M/z]⁺。

BB 10

5- (azetidin-3-yl) -2- (2-chlorophenoxy) pyridine 4-methylbenzenesulfonic acid

Step 1: 3- (6- (2-chlorophenoxy) pyridin-3-yl) azetidine-1-carboxylic acid tert-butyl ester

The product was obtained in analogy to BB 3/step 1 starting from 5-bromo-2- (2-chlorophenoxy) pyridine (CAS RN 1240670-82-9) and 3-bromoazetidine-1-carboxylic acid tert-butyl ester (CAS RN 1064194-10-0) to obtain the desired compound as a yellow oil (0.44g, 48%). Ms (esi): m/z 361.2[ M + H ]]⁺。

Step 2: 5- (aza ring)Cyclobut-3-yl) -2- (2-chlorophenoxy) pyridine 4-methylbenzenesulfonic acid

To a solution of tert-butyl 3- (6- (2-chlorophenoxy) pyridin-3-yl) azetidine-1-carboxylate (436mg, 1.21mmol, 1.0 equiv.) in ethyl acetate (6mL) was added 4-methylbenzenesulfonic acid hydrate (237mg, 1.24mmol, 1.03 equiv.), and the mixture was heated to reflux for 18 h. The suspension was cooled in a refrigerator at 0 ℃ for 1h and filtered. The precipitate was washed with diethyl ether and dried to give the title compound as a white solid (470mg, 89%). Ms (esi): 261.1[ M + H ] M/z]⁺。

BB 11

2- [ 2-fluoro-4- (trifluoromethyl) phenoxy ] -7-azaspiro [3.5] nonane 2, 2, 2-trifluoroacetic acid

Step 1: 2- [ 2-fluoro-4- (trifluoromethyl) phenoxy]-7-azaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester

To 2-hydroxy-7-azaspiro [3.5]]To a solution of tert-butyl nonane-7-carboxylate (442mg, 1.83mmol, 1.0 equiv.; CAS RN 240401-28-9) in THF (8mL) was added 2-fluoro-4- (trifluoromethyl) phenol (330mg, 1.83mmol, 1.0 equiv.; CAS RN 77227-78-2) and triphenylphosphine (529mg, 2.02mmol, 1.1 equiv.). After stirring at room temperature for 5min, the solution was cooled in an ice bath and DEAD (351mg, 319. mu.l, 2.02mmol, 1.1 equiv.) was added dropwise over 10 min. After stirring in the ice bath for 1h, the mixture was stirred at room temperature for a further 5 h. The reaction mixture was poured into water and diethyl ether, and the layers were separated. The organic layer was washed with water, aqueous NaOH (1M) and brine, MgSO₄Dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using the MPLC system, eluting with a gradient of n-heptane to ethyl acetate (100: 0 to 60: 40) to give the title compound as a colorless solid (0.63g, 85%). Ms (esi): 348.1[ M +2H-tBu ] M/z]⁺。

Step 2: 2- [ 2-fluoro-4- (trifluoromethyl) phenoxy]-7-azaspiro [3.5]Nonane 2, 2, 2-trifluoroacetic acid

To 2- [ 2-fluoro-4- (trifluoromethyl) phenoxy group]-7-azaspiro [3.5]To a solution of tert-butyl nonane-7-carboxylate (70mg, 174. mu. mol, 1.0 eq) in DCM (1mL) was added TFA (66.8. mu.l, 868. mu. mol, 5.0 eq) and the mixture was stirred at room temperature for 20 h. The solution was evaporated to give the title compound as a colourless solid (73mg, 100%). Ms (esi): m/z 304.2[ M + H%]⁺。

Example 32

The compounds of formula (Ia) or (Ib) can be used in a manner known per se as active ingredients for the production of tablets of the following compositions:

example 33

The compounds of formula (Ia) or (Ib) can be used in a manner known per se as active ingredients for the production of capsules of the following compositions:

Claims (31)

1. a compound of formula (Ia) or (Ib)

Or a pharmaceutically acceptable salt thereof,

wherein:

a is by R^AA substituted 3-to 14-membered heterocycle;

b is by R¹、R²And R³Substituted C₆-C₁₄-aryl or 5-to 14-membered heteroaryl;

l is selected from the group consisting of a covalent bond, -C.ident.C-, -CHR^L-、-CH²CHR^L-、-O-、-OCH₂-and-CH₂O-; and is

R¹、R²And R³Independently selected from hydrogen, halogen, cyano, C₁-C₆-alkylsulfonyl, R^bR^cN、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄-aryl, C₃-C₁₀-cycloalkyl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy, wherein said C is₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, 3-to 14-membered heterocyclyl, 5-to 14-membered heteroaryl, C₆-C₁₄Aryloxy group, C₃-C₁₀-cycloalkoxy, 3-to 14-membered heterocyclyloxy and 5-to 14-membered heteroaryloxy are optionally independently selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy and carbamoyl substituted with one or more substituents;

R^Aselected from hydrogen and C₁-C₆-an alkyl group;

R^band R^cIndependently selected from hydrogen, C₁-C₆-alkyl and C₆-C₁₄-an aryl group; and is

R^LSelected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆Alkyl, alkoxy-C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₆-C₁₄Aryl and halo-C₆-C₁₄-an aryl group.

2. The compound of formula (Ia) or (Ib) according to claim 1, wherein the compound of formula (Ia) or (Ib) is not selected from:

(4aS, 8aS) -6- [4- [ [4- (trifluoromethyl) phenyl ] methyl ] piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one;

(4aR, 8aR) -6- [4- [ [4- (trifluoromethyl) phenyl ] methyl ] piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one; and

rac- (4aS, 8aS) -6- [4- (2-methylallyl) piperidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one (CAS 1941372-36-6).

3. A compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein a is azetidine or 7-azaspiro [3.5]]Nonan-7-yl and R^AIs hydrogen.

4. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein B is substituted with R¹、R²And R³A substituted phenyl group.

5. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

l is selected from the group consisting of a covalent bond, -CHR^L-、-CH₂CH₂-、-O-、-OCH₂-and-CH₂O-; and is

R^LIs hydrogen or halo-C₆-C₁₄-an aryl group.

6. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond, -O-, -CH₂-、-CH₂CH₂-and-CH₂O-。

7. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond or-O-.

8. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl, C₆-C₁₄Aryloxy group and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl.

9. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C₆-C₁₄-aryloxy, halo-C₁-C₆-alkyl and halogenated-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group.

10. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from phenoxy, CF₃And (trifluoromethyl) cyclopropyl.

11. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen and halogen.

12. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or fluorine.

13. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R³Is hydrogen.

14. A compound of formula (Ia) or (Ib) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

l is selected from the group consisting of a covalent bond, -CH₂CH₂-、-CHR^L-, -O-and-CH₂O-；

R^LIs hydrogen or halo-C₆-C₁₄-an aryl group;

R¹selected from halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, hydroxy-C₁-C₆Alkyl radical, C₆-C₁₄Aryloxy group, C₆-C₁₄-aryl and C₃-C₁₀-cycloalkyl, wherein said C₃-C₁₀-cycloalkyl, C₆-C₁₄Aryloxy group and C₆-C₁₄Aryl is independently selected from halogen and halo-C₁-C₆-1-2 substituent substitutions of alkyl; and is

R²Selected from hydrogen and halogen.

15. A compound of formula (Ia) or (Ib) according to claim 1, wherein:

a is a 3-to 14-membered heterocyclic ring;

b is by R¹And R²Substituted C₆-C₁₄-an aryl group;

l is a covalent bond or-O-;

R¹is selected from C₆-C₁₄-aryloxy, halo-C₁-C₆-alkyl and halogenated-C₁-C₆-alkyl substituted C₃-C₁₀-a cycloalkyl group; and is

R²Is hydrogen or halogen.

16. A compound of formula (Ia) or (Ib) according to claim 1, wherein:

a is azetidine or 7-azaspiro [3.5] nonan-7-yl;

b is by R¹And R²Substituted phenyl;

l is selected from the group consisting of a covalent bond, -CH₂-or-O-;

R¹selected from phenoxy, CF₃And (trifluoromethyl) cyclopropyl; and is

R²Is hydrogen or fluorine.

17. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 16, selected from the compounds disclosed in table 1, or a pharmaceutically acceptable salt thereof.

18. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 16, selected from:

(4aR, 8aR) -6- [3- [4- [1- (trifluoromethyl) cyclopropyl ] phenyl ] azetidine-1-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

(4aS, 8aS) -6- (3- (4-phenoxyphenyl) azetidine-1-carbonyl) hexahydro-2H-pyrido [4, 3-b ] [1, 4] oxazin-3 (4H) -one

To know

(-) -or (+) -trans-6- [2- [ 2-fluoro-4- (trifluoromethyl) phenoxy ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4, 4a, 5, 7, 8, 8 a-hexahydropyrido [4, 3-b ] [1, 4] oxazin-3-one

19. A process for the production of a compound of formula (Ia) or (Ib) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, which process comprises:

reacting the first amine 4a, 5, 6, 7, 8, 8 a-hexahydro-4H-pyrido [4, 3-b ] [1, 4] oxazin-3-one (1)

With a second amine of formula 2, wherein A, L and B are as defined in any one of claims 1 to 18,

in the presence of a base and a urea-forming agent,

to form said compound of formula (Ia) or (Ib).

20. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, produced according to the process of claim 19.

21. A compound of formula (Ia) or (Ib) according to any one of claims 1 to 18 and claim 20, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

22. A pharmaceutical composition comprising a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 and claim 20, and a therapeutically inert carrier.

23. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 and 20 or a pharmaceutical composition according to claim 22 for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

24. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 and 20 or a pharmaceutical composition according to claim 22 for the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasm associated with pain, abdominal pain associated with irritable bowel syndrome and/or visceral pain in a mammal.

25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 and 20 or a pharmaceutical composition according to claim 22 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 and 20 or a pharmaceutical composition according to claim 22 for use in the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-associated spasm, abdominal pain associated with irritable bowel syndrome and/or visceral pain in a mammal.

27. Use of a compound of formula (I) according to any one of claims 1 to 18 and claim 20, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal.

28. Use of a compound of formula (I) according to any one of claims 1 to 18 and claim 20, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasm associated with pain, abdominal pain associated with irritable bowel syndrome and/or visceral pain in a mammal.

29. A method for the treatment or prophylaxis of neuroinflammation, neurodegenerative disease, pain, cancer, psychiatric disorders and/or inflammatory bowel disease in a mammal, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18 and claim 20, or a pharmaceutical composition as claimed in claim 22.

30. A method for the treatment or prophylaxis of multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain associated with irritable bowel syndrome and/or visceral pain in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 and 20, or a pharmaceutical composition according to claim 22.

31. The invention as hereinbefore described.